The itchy, red, and swollen reactions characteristic of allergies are driven by mast cells—quick-acting immune system sentinels that deploy histamine-filled granules when they sense a potential threat.
Now, scientists at Washington University School of Medicine in St. Louis have discovered that these same cells, often associated with allergic responses, can also play a protective role for the brain against bacterial and viral threats. Using mice as test subjects, researchers found that mast cells function as gatekeepers by blocking entry points through which waste fluid exits the brain, responding to pathogens and sealing off access when invaders are detected.
The research was published in Cell, suggesting significant implications for the prevention or treatment of brain infections.
Cell"This discovery opens up a new path for developing interventions that could protect the brain from infection," stated senior author Jonathan Kipnis, Ph.D., the Alan A. and Edith L. Wolff Distinguished Professor of Pathology & Immunology at WashU Medicine and a BJC Investigator.
"Understanding how mast cells shield the brain allows us to explore ways to enhance their function during infectious threats."
Among the targeted infections are bacterial meningitis, a potentially fatal infection affecting the meninges—the tissue layers that enwrap the brain beneath the skull.
Tiny passages within these layers create channels for fluid waste to exit from the brain into lymphatic vessels where immune cells patrol. However, these openings also provide potential entry points for bacteria.
Kipnis's team discovered the existence of lymph vessels in the dura mater—the outer tissue covering of the mouse brain—where brain fluid travels through minute gates.
To better understand how such fluid flow is regulated, the Kipnis lab partnered with Felipe Almeida de Pinho Ribeiro, Ph.D., an assistant professor of medicine at WashU Medicine who focuses on neuroimmune interactions contributing to human disease.
Working alongside Tornike Mamuladze, MD, an immunology graduate student in Kipnis's laboratory, they found that mice infected with Streptococcus agalactiae or S. pneumoniae—types of bacteria causing meningitis—showed reduced brain fluid flow through these gates compared to healthy mice.
The team discovered that the presence of bacteria in the surrounding tissues triggered mast cells to release histamine-containing granules that caused veins passing through the minute gates to widen.
By expanding and temporarily blocking the pathways normally used by brain fluid, the enlarged veins also prevented bacterial entry into the brain, protecting it from infection.
The study further revealed that activated mast cells trigger a rapid immune response, recruiting neutrophil immune cells to eliminate pathogens in infected tissues.
Lacking mast cells permitted more bacterial entry through the gates and into the brain; however, heightening mast cell activity before an infection was found to reduce bacteria levels.
The researchers also observed increased West Nile virus presence within the brains of mice lacking mast cells, suggesting viral pathogens are similarly thwarted by these cells.
"Boosting mast cell function may aid in safeguarding the brain from both bacterial and viral infections," said Kipnis. "However, mast cell activation is a double-edged sword; prolonged activation can impede fluid movement, potentially causing waste like amyloid beta to accumulate in the brain."
The team plans future work investigating whether chronic mast cell activation may negatively impact Alzheimer’s disease, characterized by amyloid-beta accumulation.
"Mast cells play an essential role within the brain," said Mamuladze, the study's first author. "Gaining insight into targeting their function at the brain's entry points to exclude pathogens while allowing waste removal will be vital for preserving brain health."